title: Rare nonsynonymous exonic variants in addiction and behavioral disinhibition.
abstract: BACKGROUND
  Substance use is heritable, but few common genetic variants have been associated with these behaviors. Rare nonsynonymous exonic variants can now be efficiently genotyped, allowing exome-wide association tests. We identified and tested 111,592 nonsynonymous exonic variants for association with behavioral disinhibition and the use/misuse of nicotine, alcohol, and illicit drugs.
  
  
  METHODS
  Comprehensive genotyping of exonic variation combined with single-variant and gene-based tests of association was conducted in 7181 individuals; 172 candidate addiction genes were evaluated in greater detail. We also evaluated the aggregate effects of nonsynonymous variants on these phenotypes using Genome-wide Complex Trait Analysis.
  
  
  RESULTS
  No variant or gene was significantly associated with any phenotype. No association was found for any of the 172 candidate genes, even at reduced significance thresholds. All nonsynonymous variants jointly accounted for 35% of the heritability in illicit drug use and, when combined with common variants from a genome-wide array, accounted for 84% of the heritability.
  
  
  CONCLUSIONS
  Rare nonsynonymous variants may be important in etiology of illicit drug use, but detection of individual variants will require very large samples.
authors.affiliation: Center for Statistical Genetics (SIV, SF, GRA), Department of Biostatistics, University of Michigan, Ann Arbor, Michigan. Electronic address: svrieze@umich.edu.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Vrieze
authors.affiliation: Center for Statistical Genetics (SIV, SF, GRA), Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Psychology (MBM, WGI, MM), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Miller
authors.affiliation: Department of Psychiatry (BMH), University of Michigan, Ann Arbor, Michigan.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Hicks
authors.affiliation: Department of Laboratory Medicine and Pathology (NP), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.affiliation: Center for Statistical Genetics (SIV, SF, GRA), Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Department of Psychology (MBM, WGI, MM), University of Minnesota, Minneapolis, Minnesota.
authors.forename: William G
authors.initials: WG
authors.lastname: Iacono
authors.affiliation: Department of Psychology (MBM, WGI, MM), University of Minnesota, Minneapolis, Minnesota.
authors.forename: Matt
authors.initials: M
authors.lastname: McGue
mesh_terms: D000293:Adolescent; D000328:Adult; D005091:Exons / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019966:Substance-Related Disorders / Q000235:genetics*; D055815:Young Adult
keywords: Addiction; alcohol; behavioral disinhibition; drug; exome; nonsynonymous; tobacco